Agent for potentiating nerve growth factor activity containing 1,2-ethanediol derivative or salt thereof

ABSTRACT

A 1,2-ethanediol derivative represented by the general formula  I! or its salt: ##STR1## has a NGF activity-potentiating effect and is useful as a remedy for various diseases caused by degeneration of central nervous system or peripheral nervous system such as senile dementia of Alzheimer type, Huntington&#39;s chorea, various neuropathies, Riley-Day syndrome, traumatic nerve injury, amyotrophic lateral sclerosis (ALS) and the like.

This application is a division of application Ser. No. 08/809,407, filedApr. 23, 1997, now U.S. Pat. No. 5,807,887, which is a 371 of PCT/JP95/02162, filed Oct. 20, 1995.

TECHNICAL FIELD

This invention relates to a 1,2-ethanediol derivative or a salt thereofwhich potentiates the activity of a nerve growth factor (referred tohereinafter as NGF).

BACKGROUND ART

It has been known that NGF acts as a survival and maintenance as well asneurite outgrowth factor for sympathetic neurons and sensory neurons inthe peripheral nervous system Physiol. Rev., vol. 60, pages 1284-1335(1980) and Ann. Rev. Biochem., vol. 51, pages 845-868 (1982)! and thathigh NGF levels were found in the regions innervated by themagnocellular neurons (hippocampus, neocortex, olfactory bulb), and inthe regions containing the cell bodies of these neurons (septum, nucleusof the diagonal band of Broca, nucleus basalise of Meynert) and that NGFacts as neurotrophic factor for magnocellular cholinergic neurons EMBOJ., vol. 4, pages 1389-1393 (1985)!.

NGF has also been drawing attention in terms of relation to centralnervous diseases such as senile dementia of Alzheimer type Science, vol.232, page 1341 (1986)!, Huntington's chorea Neurosci. Lett., vol. 40,No. 2, pages 161-164 (1992)!, and to peripheral nervous diseases such asvarious neuropathies {diabetic neuropathy Brain Res., vol. 634, pages7-12 (1994)!, neuropathy caused by drugs (Brain Res., vol. 640, pages195-204 (1994)! and the like}, Riley-Day syndrome Japanese J. ofClinical Medicine, vol. 50, No. 4, pages 178-183 (1992)!, traumaticneuropathy Pharmacol. Ther., vol. 65, No. 1, pages 1-16 (1995)!,amyotrophic lateral sclerosis (ALS) Nature Medicine, vol. 1, No. 2,pages 168-172 (1995) and the like.

An attempt has been made to use NGF or a NGF-like substance for thetreatment of central and peripheral nervous diseases described aboveBrain and Nerve, vol. 43, No. 12, pages 1101-1112 (1991) and the like!.However, these substances are all proteins, and when they are used asdrugs, their stability, antigenicity and the like will become a problem.Therefore, a compound useful as a drug for potentiating the NGF activityhas been desired.

DISCLOSURE OF THE INVENTION

Under such circumstances, the present inventors have made extensiveresearch and have consequently found that a 1,2-ethanediol derivativerepresented by the following general formula I! or a salt thereofpotentiates the NGF activity: ##STR2## wherein R¹ represents asubstituted or unsubstituted phenyl, naphthyl, indanyl, indenyl,tetrahydronaphthyl or heterocyclic group; R² represents a hydrogen atom,a lower alkyl group or a hydroxyl-protecting group; R³ represents ahydrogen atom or a lower alkyl group; nR⁴ 's may be the same as ordifferent from one another and each represents a hydrogen atom or alower alkyl group; nR⁵ 's may be the same as or different from oneanother and each represents a hydrogen atom or a lower alkyl group; R⁶represents a substituted or unsubstituted amino or nitrogen-containingheterocyclic group or an ammonio group; and n represents 0 or an integerof 1 to 6.

This invention is explained in detail below.

In the present specification, unless otherwise specified, the terms usedherein have the following meanings.

The term "halogen atom" means fluorine atom, chlorine atom, bromine atomor iodine atom. The term "lower alkyl group" means a C₁₋₆ alkyl groupsuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, pentyl, hexyl or the like. The term "lower alkenyl group"means a C₂₋₆ alkenyl group such as vinyl, propenyl, butenyl, pentenyl,hexenyl or the like. The term "lower alkenyloxy group" means a C₂₋₆alkenyl--O-- group. The term "cycloalkyl group" means a C₃₋₆ cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or thelike. The term "lower alkoxy group" means a C₁₋₆ alkyl--O-- group. Theterm "lower alkylthio group" means a C₁₋₆ alkyl--S-- group. The term"halo-lower alkyl group" means a halogen--C₁₋₆ alkyl group. The term"aryl group" means a phenyl, naphthyl, indanyl or indenyl group. Theterm "aryloxy group" means an aryl--O-- group. The term "ar-lower alkylgroup" means an ar--C₁₋₄ alkyl group such as benzyl, diphenylmethyl,trityl, phenethyl or the like. The term "ar-lower alkoxy group" means anar--C₁₋₄ alkyl--O-- group. The term "ar-lower alkylthio group" means anar--C₁₋₄ alkyl--S-- group. The term "ar-lower alkenyl group" means anar--C₂₋₄ alkenyl group. The term "lower alkylenedioxy group" means aC₁₋₄ alkylenedioxy group such as methylenedioxy, ethylenedioxy or thelike. The term "lower acyl group" means a C₁₋₆ acyl group such asformyl, acetyl, butyryl or the like. The term "aroyl group" means anaryl--CO-- group. The term "lower alkyl-sulfonyl group" means a C₁₋₆alkyl--SO₂ group. The term "ar-lower alkylsulfonyl group" means anar--C₁₋₆ alkyl--SO₂ -- group. The term "arylsulfonyl group" means anaryl--SO₂ -- group. The term "arylsulfonylamino group" means anaryl--SO₂ NH₂ -- group. The term "lower alkylsulfonylamino group" meansa C₁₋₆ alkyl--SO₂ NH-- group. The term "di-lower alkyl amino group"means a (C₁₋₆ alkyl)₂ N-- group such as dimethyl-amino, diethylamino orthe like. The term "ammonio group" means a tri-lower alkylammonio groupsuch as trimethylammonio, triethylammonio or the like. The term"nitrogen-containing heterocyclic group" means a hetero-cyclic group ofa 5-membered or 6-membered ring, fused ring or bridged ring containingat least one nitrogen atom as hetero atom forming the ring which mayfurther contain at least one oxygen or sulfur atom such as pyrrolyl,pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl,tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl,quinolidinyl, tetrahydroquinolinyl, tetrahydro-isoquinolinyl,quinuclidinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl,imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl,indazolyl or the like. The term "heterocyclic group" means theabove-mentioned nitrogen-containing heterocyclic group or a 5-memberedor 6-membered ring, a fused ring or a bridged ring containing at leastone hetero atom selected from the group consisting of nitrogen, oxygenor sulfur atom which may contain at least one oxygen or sulfur atom ashetero atom forming the ring such as furyl, thienyl, benzothienyl,pyranyl, isobenzofuranyl, oxazolyl, benzo-furanyl, indolyl,benzimidazolyl, benzoxazolyl, benzo-thiazolyl, quinoxalyl,dihydroquinoxalinyl, 2,3-dihydro-benzothienyl, 2,3-dihydrobenzopyrrolyl,2,3-dihydro-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzob!dioxanyl, imidazo 2,3-a!pyridyl, benzo b!piperazinyl, chromenyl,isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl,isoindolyl, isoquinolyl or the like. The term "heterocyclic carbonylgroup" means a heterocyclic--CO-- group.

The substituents of the phenyl, naphthyl, indanyl, indenyl,tetrahydronaphthyl and heterocyclic groups in R¹ include, for example,halogen atoms; substituted or unsubstituted amino, lower alkyl, aryl,ar-lower alkyl, lower alkoxy, ar-lower alkoxy, aryloxy, carbamoyloxy,lower alkylthio, lower alkenyl, lower alkenyloxy, ar-lower alkylthio,ar-lower alkylsulfonyl, arylsulfonyl, lower alkylsulfonylmaino,arylsulfonylamino and heterocyclic groups; protected amino groups;protected or unprotected hydroxyl groups; nitro group; oxo group; loweralkylenedioxy groups and the like.

The substituents of the lower alkyl, aryl, ar-lower alkyl, lower alkoxy,ar-lower alkoxy, aryloxy, carbamoyloxy, lower alkylthio, lower alkenyl,lower alkenyloxy, ar-lower alkylthio, ar-lower alkylsulfonyl,arylsulfonyl, lower alkylsulfonylmaino, arylsulfonylamino andheterocyclic groups in the substituent of the phenyl, naphthyl, indanyl,indenyl, tetrahydronaphthyl and heterocyclic groups of R¹ ; and thesubstituents of the nitrogen-containing heterocyclic group in R⁶ includehalogen atoms, protected or unprotected hydroxyl groups, protected orunprotected carboxyl groups, protected or unprotected amino groups,lower alkyl groups which is unsubstituted or substituted by a protectedor unprotected hydroxyl group, halogen-substituted or unsubstituted arylgroups, halogen-substituted or unsubstituted aroyl groups, lower alkoxygroup-substituted or unsubstituted lower alkoxy groups, halo-lower alkylgroups, lower acyl groups, ar-lower alkyl groups, ar-lower alkenylgroups, heterocyclic groups, heterocyclic carbonyl groups, oxo group,lower alkyl-sulfonyl groups and arylsulfonyl groups and these may besubstituted by at least one of these substituents.

The substituents of the amino group in R¹ and the substituted aminogroup in R⁶ include protected or unprotected hydroxyl groups, loweralkyl groups which are unsubstituted or substituted by a protected orunprotected hydroxyl or carboxyl group, cycloalkyl groups, aryl groups,lower acyl groups, ar-lower alkyl groups, heterocyclic groups, oxogroup-substituted or unsubstituted heterocyclic carbonyl groups,adamantyl group, lower alkylsulfonyl groups and arylsulfonyl groups, andthese may be substituted by at least one of these substituents.

Hydroxyl-protecting group of R² and the protective group of hydroxyl,carboxyl and amino groups included in the substituents include usualhydroxyl- , carboxyl- and amino-protecting groups mentioned in"Protective Groups in Organic Synthesis" by Theodra W. Greene (1981),published by John Wiley & Sons, Inc. and in particular, as thehydroxyl-protecting group, there are mentioned lower alkyl groups, loweracyl groups, tetrahydropyranyl group and substituted or unsubstitutedar-lower alkyl groups such as benzyl.

The salt of the 1,2-ethanediol derivative represented by the generalformula I! may be any pharmaceutically acceptable salt and includessalts with mineral acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid and the like; salts with carboxylic acidssuch as formic acid, acetic acid, oxalic acid, fumaric acid, maleicacid, malic acid, tartaric acid, aspartic acid and the like; salts withsulfonic acids, such as methanesulfonic acid, benzene-sulfonic acid,p-toluenesulfonic acid, naphthalene-sulfonic acid and the like; saltswith alkali metals such as sodium, potassium and the like; etc.

When the 1,2-ethanediol derivative represented by the general formula I!or its salt has isomers (for example, optical isomers, geometricalisomers, tautomers and the like), this invention includes all theseisomers, and also include hydrates, solvates and all crystal forms ofthe above compound or its salt.

The 1,2-ethanediol derivative represented by the general formula I! orits salt can be formed into a preparation such as tablet, capsule,powder, granules, fine granules, pill, suspension, emulsion, solution,syrup, injection or the like using a pharmaceutically acceptablepreparation adjuvant such as excipient, carrier, diluent or the like ina conventional manner, and the resulting preparation can be administeredorally or parenterally. The administration route, dosage and number ofadministrations may be adequately varied depending upon the age, weightand symptom of a patient and in the case of oral administration, thedosage is usually 0.01 to 500 mg/day per adult and this may beadministered in one to several portions.

An explanation is made below of a process for producing the1,2-ethanediol derivative represented by the general formula I! or itssalt.

The 1,2-ethandiol derivative represented by the general formula I! orits salt can be produced by the methods described in JP-A-3-47,158;JP-A-3-197,422; JP-A- 3-232,830; and JP-A-4-95,070 and the like ormethods known per se or in appropriate combinations thereof, forexample, according to each of the following production processes.##STR3## wherein R¹, R², R³, R⁴, R⁵, R⁶ and n have the same meanings asdescribed above, * represents an asymmetric carbon and X¹ and X²represent halogen atoms.

Production Process 1

(1) A compound of the general formula IV! or its salt can be produced byreacting a compound of the general formula II! with a compound of thegeneral formula III!.

In this reaction, any solvent may be used as far as it does notadversely affect the reaction, and the solvent includes ethers such asdiethyl ether, tetra-hydrofuran, dioxane and the like; aromatichydrocarbons such as benzene, toluene and the like; etc. These solventsmay be used alone or in admixture of two or more.

In the above reaction, the amount of the compound of the general formulaIII! used is 0.8 to 100 moles, preferably 0.8 to 10 moles, per mole ofthe compound of the general formula II!.

Said reaction may be carried out usually at a temperature of -78° C. to+100° C., preferably -78° C. to +50° C., for a period of 5 minutes to 24hours.

The compound of the general formula IV! or its salt thus obtained may beused in the subsequent reaction as it is without being isolated.

Incidentally, the compound of the general formula III! used here can beproduced by a method known per se, for example, the method described inBull. Soc. Chim. Fr., 1967(5), pages 1533-1540.

(2) The compound of the general formula I! or its salt can be producedby reacting the compound of the general formula IV! or its salt with acompound of the general formula V! or its salt in the presence orabsence of a catalyst and in the presence or absence of a base.

In this reaction, any solvent may be used as far as it does notadversely affect the reaction, and the solvent includes halogenatedhydrocarbons such as methylene chloride, chloroform and the like; etherssuch as tetrahydrofuran, dioxane and the like; alcohols such as ethanol,propanol, butanol and the like; nitrites such as acetonitrile and thelike; amides such as N,N-dimethylformamide and the like; water; etc.These solvents may be used alone or in admixture of two or more.

The optionally used catalyst includes, for example, potassium iodide,sodium iodide and the like.

The amount of the catalyst used is 0.1 to 1 mole per mole of thecompound of the general formula IV! or its salt.

The optionally used base includes organic and inorganic bases such astriethylamine, diisopropylethyl-amine, 1,8-diazobicyclo5.4.0!undec-7-ene (DBU), pyridine, potassium tert-butoxide, sodiumcarbonate, potassium carbonate, sodium hydride and the like. Also, thecompound of the general formula V! or its salt can be used as the base.

The amount of the compound of the general formula V! or its salt or thebase used is at least one mole, preferably 1 to 20 moles, per mole ofthe compound of the general formula IV! or its salt.

Said reaction may be carried out usually at a temperature of 10° C. to150° C., preferably 20° C. to 100° C., for a period of 10 minutes to 20hours.

The compounds or bases used in each of the above production processescan also be used as solvents depending upon their properties.

When the compounds of the general formulas II!, III!, IV! and V! in theabove-mentioned production processes have isomers (for example, opticalisomers, geometrical isomers, tautomers and the like), all of them canbe used, and also, they can be used in the form of hydrates and solvatesand in all crystal forms.

When the compounds of the general formulas II!, III!, IV! and V! have ahydroxyl group, an amino group or a carboxyl group, said hydroxyl, aminoor carboxyl group may previously be protected with a conventionalprotective group and, after the reaction, the protective group can, ifnecessary, be removed in a manner known per se.

Production Process 2

(1) A compound represented by the general formula VI! or its salt can beproduced by oxidizing the compound represented by the general formulaIV! or its salt by a conventional method as described in "ModernSynthetic Reactions", Second Edition by Herbert O. House (1972)published by W. A. Benjamin, Inc., or the like.

Any solvent may be used in this reaction as far as it does not adverselyaffect the reaction, and the solvent includes ethers such as diethylether, tetra-hydrofuran, dioxane and the like; aromatic hydrocarbonssuch as benzene, toluene and the like; etc. These solvents may be usedalone or in admixture of two or more.

The compound represented by the general formula VI! or its salt thusobtained can be used in the subsequent reaction as it is without beingisolated.

(2) A compound represented by the general formula IVa! or its salt canbe produced by reducing the compound represented by the general formulaVI! or its salt in the presence or absence of a catalyst and in thepresence or absence of a base by a method known per se, for example, themethod described in Tetrahedron Letters, vol. 33, No. 29, page 4102, orthe like.

(3) The compound of the general formula I! or its salt can be producedby reacting the compound represented by the general formula IVa! or itssalt with the compound represented by the general formula V! in thepresence or absence of a catalyst and in the presence or absence of abase in the same manner as in the Production Process 1 (2) mentionedabove.

The 1,2-ethanediol derivative represented by the general formula I! orits salt thus obtained can be purified and isolated by a conventionalmethod such as extraction, crystallization, distillation, columnchromatography or the like. Also, the 1,2-ethanediol derivativerepresented by the general formula I! or its salt can be converted toanother 1,2-ethanediol derivative or its salt by an adequate combinationof known methods per se such as oxidation reaction, reduction reaction,addition reaction, acylation reaction, alkylation reaction,sulfonylation reaction, deacylation reaction, substitution reaction,dehydration reaction, hydrolysis reaction and the like.

Reference Examples and Production Examples are shown below for morespecifically explaining the processes for producing the compounds ofthis invention.

In the following Reference Examples and Production Examples, the mixingratio of the solvents is all indicated in volume basis. In columnchromatographic purification, Silica gel (70-230 meshes, mfd. by Merck &Co., Inc.) is used as a support. In moderate pressure columnchromatographic purification, LC Sorb SP-A-Si (mfd. by Chemco) are usedas a support.

The compound of the general formula II!, a starting material forproducing the compound of the present invention, is known per se.Otherwise, it can be prepared by a method known per se or an adequatecombination of methods known per se in accordance with the followingReference Examples.

REFERENCE EXAMPLE 1

(1) In 250 ml of water is suspended 25.0 g of 3-fluoro-4-methylaniline,and 34.7 ml of conc. hydro-chloric acid is added to the suspension.Thereafter, the resulting mixture is cooled to 5° C. To this mixture isdropwise added a solution of 15.2 g of sodium nitrite in 20 ml of waterat a temperature of 5° C. to 10° C. over one hour. The reaction mixturethus obtained is dropwise added to a solution of 64.0 g of potassiumO-ethyl dithiocarbonate in 200 ml of water at a temperature of 50° C. to60° C. over one hour. The resulting reaction mixture is cooled to roomtemperature, and thereafter, 300 ml of ethyl acetate is added thereto.Thereafter, the resulting organic layer is separated, washed with asaturated saline solution and then dried over anhydrous magnesiumsulfate. Then, the solvent is removed by distillation under reducedpressure, to obtain brown, oily O-ethyl S-(3-fluoro-4-methyl)phenyldithiocarbonate.

(2) To a solution of O-ethyl S-(3-fluoro-4-methyl)phenyl dithiocarbonatein 150 ml of methanol is added 22.4 g of potassium hydroxide at roomtemperature under a nitrogen atmosphere. The resulting mixture isstirred at room temperature for five hours. Thereafter, 34.8 ml ofbromoacetaldehyde diethyl acetal is added to the thus stirred mixture.The resulting mixture is refluxed for six hours and then cooled.Thereafter, insolubles are removed from the thus cooled mixture byfiltration. The resulting filtrate is concentrated under reducedpressure. To the residue obtained are added 300 ml of water and 150 mlof ethyl acetate, and the resulting organic layer is separated, washedwith a saturated saline solution and dried over anhydrous magnesiumsulfate. Thereafter, the solvent is removed from the thus dried layer bydistillation under reduced pressure. The residue thus obtained ispurified by a column chromatography eluent:hexane:ethyl acetate=10:1!,to obtain 43.6 g of oily1,1-diethoxy-2-(3-fluoro-4-methylphenylthio)ethane.

NMR (CDCl₃) δ value: 1.19 (6H, t, J=7.0Hz), 2.22 (3H, d, J=2.0Hz), 3.09(2H, d, J=5.4Hz), 3.58 (2H, q, J=7.0Hz), 3.63 (2H, q, J=7.0Hz), 4.63(1H, t, J=5.4Hz), 6.9-7.3 (3H, m)

(3) To a solution of 43.6 g of1,1-diethoxy-2-(3-fluoro-4-methylphenylthio)ethane in 400 ml of tolueneis added 80 ml of 85% phosphoric acid. The resulting solution isrefluxed for 2.5 hours using an azeotropic dehydration apparatus. Aftercooling, to the thus cooled reaction mixture are added 600 ml of waterand 200 ml of ethyl acetate, and the resulting organic layer isseparated, washed successively with water and a saturated salinesolution and then dried over anhydrous magnesium sulfate. Thereafter,the solvent is removed from the thus dried layer by distillation underreduced pressure. The residue thus obtained is purified by a columnchromatography eluent:hexane!, to obtain 15.9 g of a colorless, solidmixture of 4-fluoro-5-methyl-benzo- b!thiophene and6-fluoro-5-methyl-benzo b!thiophene.

(4) To a solution of 15.9 g of a mixture of 4-fluoro-5-methyl-benzob!thiophene and 6-fluoro-5-methyl-benzo b!thiophene in 160 ml of carbontetrachloride are added 17 g of N-bromosuccinimide and 0.31 g of2,2'-azo-bisisobutylonitrile. The resulting mixture is refluxed for twohours. After cooling, insolubles are removed from the thus cooledmixture by filtration, and the filtrate obtained is concentrated underreduced pressure. The residue obtained is suspended in 75 ml of aceticacid and 75 ml of water, and 26.8 g of hexamethylenetetramine is addedthereto, after which the resulting mixture is refluxed for two hours.After cooling, 150 ml of water and 200 ml of ethyl acetate are added tothe thus cooled mixture, and the resulting organic layer is separated,washed successively with water, an aqueous saturated sodium carbonatesolution and a saturated saline solution and then dried over anhydrousmagnesium sulfate. Thereafter, the solvent is removed from the thusdried layer by distillation under reduced pressure. The residue thusobtained is purified by a moderate pressure column chromatographyeluent:hexane:ethyl acetate=15:1!, to obtain 1.71 g of 4-fluorobenzob!thiophene-5-carbaldehyde and 5.82 g of 6-fluorobenzob!thiophene-5-carbaldehyde.

Physical properties of each of the compounds are as follows:

4-Fluorobenzo b!thiophene-5-carbaldehyde IR (KBr) cm⁻¹ : 1684 NMR(CDCl₃) δ value: 7.5-8.1 (4H, m), 10.55 (1H, s)

6-Fluorobenzo b!thiophene-5-carbaldehyde IR (KBr) cm⁻¹ : 1684 NMR(CDCl₃) δ values 7.3-7.6. (2H, m), 7.67 (1H, d, J=10.3Hz), 8.34 (1H, d,J=6.4Hz), 10.46 (1H, s)

In the same manner, the following compounds are obtained:

7-Fluorobenzo b!thiophene-5-carbaldehyde IR (KBr) cm⁻¹ : 1678 NMR(CDCl₃) δ value: 7.2-7.8 (3H, m), 8.16 (1H, s), 10.60 (1H, s)

4-Bromobenzo b!thiophene-5-carbaldehyde IR (KBr) cm⁻¹ : 1674 NMR (CDCl₃)δ value: 7.1-8.0 (4H, m), 10.54 (1H, s)

6-Bromobenzo b!thiophene-5-carbaldehyde IR (KBr) cm⁻¹ : 1681 NMR (CDCl₃)δ value: 7.3-7.6 (2H, m), 8.18 (1H, s), 8.41 (1H, s), 10.51 (1H, s)

4-Chlorobenzo b!thiophene-5-carbaldehyde IR (KBr) cm⁻¹ : 1678 NMR(CDCl₃) δ value: 7.3-8.2 (4H, m), 10.66 (1H, s)

6-Chlorobenzo b!thiophene-5-carbaldehyde IR (KBr) cm⁻¹ : 1678 NMR(CDCl₃) δ value: 7.2-7.7 (2H, m), 7.98 (1H, s), 8.42 (1H, s), 10.60 (1H,s)

Reference Example 2

(1) In a solution of 5 g of benzo b!thiophene-5-carbaldehyde in 100 mlof benzene are added 20 ml of ethylene glycol and a catalytic amount ofp-toluene-sulfonic acid, and the resulting mixture is refluxed for twohours using an azeotropic dehydration apparatus. After cooling, 200 mlof water and 100 ml of ethyl acetate are added to the thus cooledmixture, and the resulting organic layer is separated, washedsuccessively with water and a saturated saline solution and dried overanhydrous magnesium sulfate. Thereafter, the solvent is removed from thethus dried layer by distillation under reduced pressure. The residueobtained is purified by a moderate pressure column chromatographyeluent:hexane:ethyl acetate=10:1!, to obtain 6.12 g of colorless, solid5-(1,3-dioxoran-2-yl)benzo b!thiophene.

NMR (CDCl₃) δ value: 3.9-4.3 (4H, m), 5.94 (1H, s), 7.2-7.6 (3H, m),7.7-8.1 (2H, m)

(2) A solution of 1.5 g of 5-(1,3-dioxoran-2-yl)-benzo b!thiophene in 15ml of tetrahydrofuran is cooled to -40° C., at which temperature 4.55 mlof 1.6 M hexane solution of n-butyllithium is then dropwise added to thesolution. The temperature of the resulting reaction mixture is elevatedto -10° C., and then lowered to -40° C. again, at which 0.45 ml ofmethyl iodide is added to the thus re-cooled reaction mixture. Thetemperature of the resulting mixture is elevated to room temperature. 30Milliliters of water and 30 ml of ethyl acetate are added thereto, andthe resulting organic layer is separated, washed successively with waterand a saturated saline solution and dried over anhydrous magnesiumsulfate. Thereafter, the solvent is removed from the thus dried layer bydistillation under reduced pressure. The residue obtained is purified bya moderate pressure column chromatography eluent:hexane:ethylacetate=10:1!, to obtain 1.45 g of colorless, solid2-methyl-5-(1,3-dioxoran-2-yl)benzo b!thiophene.

NMR (CDCl₃) δ value: 2.55 (3H, s), 3.9-4.3 (4H, m), 5.89 (1H, s),6.9-8.0 (4H, m)

(3) A catalytic amount of p-toluenesulfonic acid is added to a solutionof 1.5 g of 2-methyl-5-(1,3-dioxoran-2-yl)benzo b!thiophene in 20 ml ofacetone at room temperature, at which temperature the resulting mixtureis stirred for 30 minutes. After the reaction, the solvent is removedfrom the reaction mixture by distillation under reduced pressure. Theresidue obtained are added 20 ml of water and 20 ml of ethyl acetate,after which the resulting organic layer is separated, washedsuccessively with water and a saturated saline solution and then driedover anhydrous magnesium sulfate. The solvent is thereafter removed fromthe thus dried layer by distillation under reduced pressure, to obtain1.15 g of colorless, solid 2-methylbenzo b!-thiophene-5-carbaldehyde.

IR (KBr) cm⁻¹ : 1694

NMR (CDCl₃) δ value: 2.60 (3H, s), 5.89 (1H, s), 7.0-8.4 (4H, m), 10.10(1H, s)

Reference Example 3

(1) To a solution of 3 g of benzo b!thiophene-5-carbaldehyde in 30 ml ofacetic acid is dropwise added 1.43 ml of bromine with ice-cooling. Thetemperature of the reaction mixture is elevated to room temperature, atwhich temperature the mixture is stirred for three hours. After thereaction, 50 ml of water and 50 ml of ethyl acetate are added to thethus stirred reaction mixture, and the resulting organic layer wasseparated, washed successively with water, a saturated aqueous sodiumhydrogencarbonate solution and a saturated saline solution and thendried over anhydrous magnesium sulfate. Thereafter, the solvent isremoved from the thus dried layer by distillation under reducedpressure. The residue obtained is purified by a moderate pressure columnchromatography eluent:hexane:ethyl acetate=20:1!, to obtain 4.2 g of3-bromobenzo b!thiophene-5-carbaldehyde.

NMR (CDCl₃) δ value: 7.5-8.4 (4H, m), 10.19 (1H, s)

(2) The same procedure as in Reference Example 2 (1) is repeated, exceptthat 3-bromobenzo b!thiophene-5-carbaldehyde is substituted for thebenzo b!thiophene-5-carbaldehyde, to obtain3-bromo-5-(1,3-dioxoran-2-yl)-benzo b!thiophene.

NMR (CDCl₃) δ value: 3.9-4.2 (4H, m), 5.93 (1H, s), 7.3-8.0 (4H, m)

(3) The same procedure as in Reference Example 2 (2) is repeated, exceptthat 3-bromo-5-(1,3-dioxoran-2-yl)benzo b!thiophene is substituted forthe 5-(1,3-dioxoran-2-yl)benzo b!thiophene and diethyl ether issubstituted for the tetrahydrofuran, to obtain 3-methyl-benzob!thiophene-5-carbaldehyde.

NMR (CDCl₃) δ value: 2.51 (3H, s), 7.0-8.4 (4H, m), 10.15 (1H, s)

Reference Example 4

The same procedure as in Reference Example 2 (2) and Reference Example 2(3) is repeated, except that N-fluorobenzenesulfonimide is substitutedfor the methyl iodide to obtain 2-fluorobenzo b!thiophene-5-carbaldehydefrom 5-(1,3-dioxoran-2-yl)benzo b!thiophene.

NMR (CDCl₃) δ value: 6.84 (1H, d J=2.0Hz), 7.6-8.4 (3H, m), 10.09 (1H,s)

Reference Example 5

The same procedure as in Reference Example 2 (2) and Reference Example 2(3) is repeated, except that 3-bromo-5-(1,3-dioxoran-2-yl)benzob!thiophene is substituted for the 5-(1,3-dioxoran-2-yl)benzob!-thiophene; diethyl ether is substituted for the tetra-hydrofuran; andN-fluorobenzenesulfonimide is substituted for the methyl iodide, toobtain 3-fluorobenzo b!-thiophene-5-carbaldehyde from3-bromo-5-(1,3-dioxoran-2-yl)benzo b!thiophene.

NMR (CDCl₃) δ value: 6.99 (1H, d, J=2.0Hz), 7.7-8.4 (3H, m), 10.14 (1H,s)

Reference Example 6

(1) To a solution of 2.0 g of 5-(1,3-dioxoran-2-yl)benzo b!thiophene in15 ml of tetrahydrofuran is added dropwise 6.06 ml of a 1.6 M hexanesolution of n-butyllithium at -78° C. The temperature of the reactionmixture was elevated to -10° C. and thereafter lowered again to -78° C.,after which 1.55 g of bromine is added to the thus re-cooled reactionmixture. The temperature of the resulting mixture is elevated to roomtemperature, and thereafter, 30 ml of water and 30 ml of ethyl acetateare added thereto. The resulting organic layer is separated, washedsuccessively with water and a saturated saline solution, and then driedover anhydrous magnesium sulfate. Thereafter, the solvent is removedfrom the thus dried layer by distillation under reduced pressure. Theresidue obtained is purified by a moderate pressure columnchromatography elueant:toluene!, to obtain 2.45 g of colorless, solid2-bromo-5-(1,3-dioxoran-2-yl)benzo- b!thiophene.

NMR (CDCl₃) δ value: 3.9-4.3 (4H, m), 5.89 (1H, s), 7.2-8.0 (4H, m)

(2) To a solution of 2.5 g of 2-bromo-5-(1,3-dioxoran-2-yl)benzob!thiophene in 50 ml of toluene are added 6.44 g of phenyltri-n-butyltinand 0.05 g of tetra-kis(triphenylphosphine)palladium (0), and theresulting mixture is refluxed under a nitrogen atmosphere for fivehours. The reaction mixture is cooled to room temperature. Thereafter,30 ml of water and 30 ml of ethyl acetate are added to the thus cooledreaction mixture. Thereafter, insolubles are removed from the resultingmixture by filtration. Thereafter, the resulting organic layer isseparated, washed successively with water and a saturated salinesolution and then dried over anhydrous magnesium sulfate. Thereafter,the solvent is removed from the thus dried layer by distillation underreduced pressure. The residue obtained is purified by a columnchromatography eluent:hexane:ethyl acetate=20:1!, to obtain 1.20 g ofcolorless, solid 2-phenyl-5-(1,3-dioxoran-2-yl)benzo b!thiophene.

(3) In the same manner as in Reference Example 2 (3), 2-phenylbenzob!thiophene-5-carbaldehyde is obtained from2-phenyl-5-(1,3-dioxoran-2-yl)benzo b!thiophene.

IR (KBr) cm⁻¹ : 1692

NMR (CDCl₃) δ value: 7.2-8.4 (9H, m), 10.13 (1H, s)

In the same manner, the following compound is obtained:

3-Phenylbenzo b!thiophene-5-carbaldehyde IR (KBr) cm⁻¹ : 1686 NMR(CDCl₃) δ value: 7.3-8.1 (8H, m), 8.37 (1H, m), 10.09 (1H, s)

Reference Example 7

(1) The same procedure as in Reference Example 1 (1) and ReferenceExample 1 (2) is repeated, except that methyl 4-amino-2-methylbenzoateis substituted for the 3-fluoro-4-methylaniline, to obtain methyl4-(2,2-diethoxyethylthio)-2-methylbenzoate.

NMR (CDCl₃) δ value: 1.20 (6H, t, J=7.0Hz), 2.57 (3H, s), 3.18 (2H, d,J=5.4Hz), 3.3-3.8 (4H, m), 3.86 (3H, s), 4.67 (1H, t, J=5.4Hz), 7.0-7.3(2H, m), 7.7-7.9 (1H, m)

(2) The same procedure as in Reference Example 1 (3) is repeated, exceptthat methyl 4-(2,2-diethoxy-ethylthio)-2-methylbenzoate is substitutedfor the 1,1-diethoxy-2-(3-fluoro-4-methylphenylthio)ethane, to obtain amixture of methyl 4-methylbenzo b!thiophene-5-carboxylate and methyl6-methylbenzo b!thiophene-5-carboxylate.

(3) In 20 ml of tetrahydrofuran is suspended 0.37 g of lithium aluminumhydride. Thereafter, a solution of 2 g of a mixture of methyl4-methylbenzo b!thiophene-5-carboxylate and methyl 6-methylbenzob!thiophene-5-carboxylate in 20 ml of tetrahydrofuran is dropwise addedto the suspension. The temperature of the resulting suspension iselevated to room temperature, and 30 ml of water and 30 ml of ethylacetate are added thereto, and the resulting mixture is filtered. Theresulting organic layer is separated, washed successively with water anda saturated saline solution and then dried over anhydrous magnesiumsulfate. The solvent is removed from the thus dried layer bydistillation under reduced pressure. The residue obtained is purified bya column chromatography eluent:hexane:ethyl acetate=10:1!, to obtain 1.7g of a mixture of 4-methylbenzo b!thiophene-5-methanol and 6-methylbenzob!thiophene-5-methanol as colorless solid.

(4) In 17 ml of chloroform is dissolved 1.7 g of a mixture of4-methylbenzo b!thiophene-5-methanol and 6-methylbenzob!thiophene-5-methanol, and 4.1 g of manganese dioxide is added theretoat room temperature. Thereafter, the resulting mixture is refluxed forone hour. After the reaction, insolubles are removed from the resultingreaction mixture by filtration and the filtrate obtained is concentratedunder reduced pressure. The residue obtained is purified by a moderatepressure column chromatography eluent:hexane:toluene=1:1!, to obtain0.65 g of 4-methylbenzo b!thiophene-5-carbaldehyde as colorless solidand 0.48 g of 6-methyl-benzo b!thiophene-5-carbaldehyde as colorlesssolid.

Physical properties of each of the compounds are as follows:

4-Methylbenzo b!thiophene-5-carbaldehyde IR (KBr) cm⁻¹ : 1673 NMR(CDCl₃) δ value: 2.95 (3H, s), 7.5-7.9 (4H, m), 10.50 (1H, s)

6-Methylbenzo b!thiophene-5-carbaldehyde IR (KBr) cm⁻¹ : 1696 NMR(CDCl₃) δ value: 2.77 (3H, s), 7.2-7.6 (2H, m), 7.75 (1H, s), 8.26 (1H,s), 10.35 (1H, s)

Reference Example 8

In the same manner as in Reference Example 6, 6-methoxybenzob!thiophene-5-carbaldehyde is obtained from 4-amino-2-methoxybenzoicacid.

NMR (CDCl₃) δ value: 3.99 (3H, 5), 7.33 (2H, m), 7.42 (1H, s), 8.28 (1H,s), 10.56 (1H, s)

Reference Example 9

(1) To a solution of 2.04 g of diisopropylamine in 30 ml oftetrahydrofuran is dropwise added 9.19 ml of 1.6 M n-hexane solution ofn-butyllithium at -20° C. At the same temperature, the resulting mixtureis stirred for one hour and then cooled to -70° C., at which temperaturea solution of 3 g of 3,5-difluorobromobenzene in 10 ml oftetrahydrofuran is dropwise added thereto over 30 minutes. Thetemperature of the resulting reaction mixture is elevated to -40° C. andthen lowered again to -70° C., at which temperature 0.97 ml of methyliodide is then added thereto. The temperature of the resulting mixtureis elevated to room temperature, and 80 ml of water and 80 ml of ethylacetate are then added thereto, after which the resulting organic layeris separated, washed successively with water and a saturated salinesolution and then dried over anhydrous magnesium sulfate. Thereafter,the solvent is removed from the thus dried layer by distillation underreduced pressure. The residue obtained is purified by a columnchromatography eluent:hexane:ethyl acetate=10:1!, to obtain 1.98 g ofcolorless, oily 4-bromo-2,6-difluorotoluene.

NMR (CDCl₃) δ value: 2.23 (3H, t, J=1.5Hz), 7.00 (2H, d, J=6.3Hz)

(2) To a solution of 1.98 g of 4-bromo-2,6-difluorotoluene in 20 ml oftetrahydrofuran is dropwise added 5.7 ml of 1.6 M n-hexane solution ofn-butyllithium at -70° C. The resulting mixture is then stirred at thesame temperature for one hour. Then, a solution of 2.88 g of2,2,2',2'-tetraethoxydiethyl disulfide in 5 ml of tetrahydrofuran isdropwise added to the thus stirred reaction mixture at the sametemperature. The temperature of the resulting mixture is elevated toroom temperature and 80 ml of water and 80 ml of ethyl acetate are addedthereto. The resulting organic layer is separated, washed successivelywith water and a saturated saline solution and then dried over anhydrousmagnesium sulfate. Thereafter, the solvent is removed from the thusdried layer by distillation under reduced pressure. The residue obtainedis purified by a column chromatography eluent:hexane:ethylacetate=20:1!, to obtain 2.1 g of colorless, oily1,1-diethoxy-2-(3,5-difluoro-4-methylphenylthio)ethane.

NMR (CDCl₃) δ value: 1.20 (3H, t, J=7.0Hz), 1.23 (3H, t, J=7.2Hz), 2.1(3H, t, J=1.7Hz), 3.10 (2H, d, J=5.6Hz), 3.4-3.9 (4H, m), 4.64 (1H, t,J=5.6Hz), 6.87 (2H, d, J=7.6Hz)

(3) The same procedure as in Reference Example 1 (3) is repeated, exceptthat 1,1-diethoxy-2-(3,5-difluoro-4-methylphenylthio)ethane issubstituted for the 1,1-diethoxy-2-(3-fluoro-4-methylphenylthio)ethane,to obtain 4,6-difluoro-5-methylbenzo b!thiophene.

NMR (CDCl₃) δ value: 2.31 (3H, t, J=1.9Hz), 7.2-7.5 (3H, m)

(4) To a solution of 0.48 g of 4,6-difluoro-5-methylbenzo b!thiophene in5 ml of carbon tetrachloride are added 0.92 g of N-bromosuccinimide and0.01 g of 2,2'-azobisisobutylonitrile, and the resulting mixture isrefluxed for 16 hours. After cooling, insolubles are removed from thethus cooled mixture by filtration, and the filtrate obtained isconcentrated under reduced pressure. The residue obtained is purified bya column chromatography eluent:hexane!, to obtain 0.18 g of colorless,solid 5-bromomethyl-4,6-difluorobenzo b!thiophene.

NMR (CDCl₃) δ value: 4.67 (2H, t, J=1.2Hz), 7.2-7.5 (3H, m)

(5) To a solution of 0.18 g of 5-bromomethyl-4,6-difluorobenzob!thiophene in 5 ml of N,N-dimethyl-formamide is added 0.23 g ofpotassium acetate, and the resulting mixture is stirred at 60° C. forone hour. The temperature of the thus stirred mixture is lowered to roomtemperature, and 10 ml of water and 10 ml of ethyl acetate are addedthereto. Thereafter, the resulting organic layer is separated, washedsuccessively with water and a saturated saline solution and then driedover anhydrous magnesium sulfate. Thereafter, the solvent is removedfrom the thus dried layer by distillation under reduced pressure, toobtain 0.14 g of colorless, oily 5-acetoxymethyl-4 , 6-difluorobenzob!thiophene.

NMR (CDCl₃) δ value: 2.07 (3H, s), 5.31 (2H, t, J=1.2Hz), 7.3-7.6 (3H,m)

(6) To a solution of 0.14 g of 5-acetoxymethyl-4,6-difluorobenzob!thiophene in 5 ml of methanol is added 0.03 g of potassium hydroxideat room temperature, and thereafter, the resulting mixture is stirred atthe same temperature for 30 minutes. After the reaction, 10 ml of waterand 10 ml of ethyl acetate are added to the thus stirred reactionmixture. The resulting organic layer is separated, washed successivelywith water and a saturated saline solution, and then dried overanhydrous magnesium sulfate. Thereafter, the solvent is removed from thethus dried layer by distillation under reduced pressure to obtain 0.12 gof colorless, oily 5-hydroxymethyl-4,6-difluorobenzo b!thiophene.

NMR (CDCl₃) δ value: 4.88 (2H, bs), 7.2-7.6 (3H, m)

(7) To a solution of 0.22 ml of oxalyl chloride in 10 ml of methylenechloride is added 0.35 ml of dimethyl sulfoxide at -78° C. Then, to theresulting solution is added dropwise a solution of 0.20 g of5-hydroxymethyl-4,6-difluorobenzo b!thiophene in 3 ml of methylenechloride. At the same temperature, the resulting mixture is stirred forone hour, and then, 0.70 ml of triethylamine is added thereto. Thetemperature of the resulting mixture is elevated to room temperature,and thereafter, 10 ml of water and 10 ml of ethyl acetate are addedthereto, after which the resulting organic layer is separated, washedsuccessively with water and a saturated saline solution and then driedover anhydrous magnesium sulfate. Then, the solvent is removed from thethus dried layer by distillation under reduced pressure. The residueobtained is purified by a column chromatography eluent:hexane!, toobtain 0.20 g of colorless, solid 4,6-difluorobenzob!thiophene-5-carbaldehyde.

IR (KBr) cm⁻¹ : 1696

NMR (CDCl₃) δ value: 7.4-7.6 (3H, m), 10.49 (1H, s)

Production Example 1

(1) To a solution of 1.6 g of 6-fluorobenzo b!thiophene-5-carbaldehydein 30 ml of tetrahydrofuran is dropwise added 10 ml of 1.6 Mtetrahydrofuran solution of 2-chloroethoxymethylmagnesium chloride at-30° C. over ten minutes, and thereafter, the resulting mixture isstirred while ice-cooling for one hour. Subsequently, the thus stirredreaction mixture is introduced into a mixture of 50 ml of ice water, 50ml of ethyl acetate and 2 g of ammonium chloride, and the resultingmixture is adjusted to pH 2 with 6 N hydrochloric acid. Thereafter, thethus pH-adjusted mixture is stirred at the same temperature for fiveminutes. Subsequently, the thus stirred reaction mixture is adjusted topH 6 with a saturated aqueous sodium hydrogencarbonate solution.Thereafter, the resulting organic layer is separated, washedsuccessively with water and a saturated saline solution, and then driedover anhydrous magnesium sulfate. The solvent is then removed from thethus dried layer by distillation under reduced pressure. The residueobtained is purified by a column chromatography eluent:toluene:ethylacetate=4:1!, to obtain 1.3 g of oily2-(2-chloroethoxy)-1-(6-fluorobenzo b!thiophen-5-yl)ethanol.

(2) A mixture of 0.61 g of 2-(2-chloroethoxy)-1-(6-fluorobenzob!thiophen-5-yl)ethanol, 3 ml of 50% aqueous diethylamine solution, 0.45mg of potassium iodide and 20 ml of ethanol is refluxed for three hours.Subsequently, 3 ml of 50% aqueous diethylamine solution is added to thethus refluxed reaction mixture, and the resulting reaction mixture isfurther refluxed for three hours. The solvent is removed from the thusrefluxed mixture by distillation under reduced pressure. To the residueobtained are added 30 ml of ethyl acetate and 30 ml of water, afterwhich the resulting mixture is adjusted to pH 1.5 with 6 N hydrochloricacid. Thereafter, the aqueous layer is separated and washed with 10 mlof ethyl acetate. 30 Milliliters of ethyl acetate is then added to thethus washed layer, after which the resulting mixture is adjusted to pH10.5 with potassium carbonate. The organic layer is separated again,washed successively with 10 ml of water and 10 ml of a saturated salinesolution, and then dried over anhydrous magnesium sulfate. The solventis then removed from the thus dried layer by distillation under reducedpressure. The residue obtained is dissolved in 6 ml of ethanol. To theresulting solution are added 0.6 ml of 5 N dried hydrochloricacid-ethanol solution and 6 ml of diethyl ether. The mixture thusobtained is stirred at room temperature for one hour. The crystalsprecipitated are collected by filtration and washed with 2 ml of aliquid mixture of diethyl ether and ethanol (1:1) and then dried, toobtain 0.28 g of 2- 2-(N,N-diethylamino)-ethoxy!-1-(6-fluorobenzob!thiophen-5-yl)ethanol hydrochloride.

Melting point: 125-126° C.

NMR (DMSO-d₆) δ value: 1.18 (6H, t, J=7.3Hz), 2.9-4.0 (10H, m), 5.0-5.4(1H, m), 5.6-5.8 (1H, m), 7.4-8.2 (4H, m)

In the same manner, the following compounds are obtained:

2- 2-(N,N-Diethylamino)ethoxy!-1-(4-fluorobenzo b!-thiophen-5-yl)ethanolhydrochloride Melting point: 127-128° C. NMR (DMSO-d₆) δ value: 1.18(6H, t, J=7.3Hz), 2.9-4.1 (10H, m), 5.1-5.4 (1H, m), 5.6-5.8 (1H, m),7.4-8.0 (4H, m)

2- 2-(N,N-Diethylamino)ethoxy!-1-(7-fluorobenzo b!-thiophen-5-yl)ethanolhydrochloride Melting point: 119-120° C. NMR (DMSO-d₆) δ value: 1.15(6H, t, J=7.3Hz), 2.8-4.0 (10H, m), 4.7-5.1 (1H, m), 5.6-5.9 (1H, m),7.1-8.0 (4H, m)

2- 2-(N,N-Diethylamino)ethoxy!-1-(2-fluorobenzo b!-thiophen-5-yl)ethanolhydrochloride Melting point: 130-131° C. NMR (DMSO-d₆) δ value: 1.17(6H, t, J=7.3Hz), 2.8-4.0 (10H, m), 4.86 (1H, m), 5.6-5.9 (1H, m),7.1-8.0 (4H, m)

2- 2-(N,N-Diethylamino)ethoxy!-1-(3-fluorobenzo b!-thiophen-5-yl)ethanolhydrochloride Melting point: 106-107° C. NMR (DMSO-d₆) δ value: 1.17(6H, t, J=7.3Hz), 2.8-4.0 (10H, m), 4.8-5.2 (1H, m), 5.4-6.0 (1H, m),7.4-8.2 (4H, m)

2- 2-(N,N-Diethylamino)ethoxy!-1-(2-methylbenzo b!-thiophen-5-yl)ethanolhydrochloride Melting point: 136-137° C. NMR (DMSO-d₆) δ value: 1.18(6H, t, J=7.3Hz), 2.54 (3H, s), 2.8-4.0 (10H, m), 4.7-5.0 (1H, m),5.3-5.8 (1H, m), 7.0-8.0 (4H, m)

2- 2-(N,N-Diethylamino)ethoxy!-1-(3-methylbenzo b!-thiophen-5-yl)ethanol1/2 fumarate Melting point: 137-138° C. NMR (DMSO-d₆) δ value: 0.99 (6H,t, J=7.3Hz), 2.3-3.1 (9H, m), 3.4-3.8 (4H, m), 4.2-5.1 (3H, m), 6.53(1H, s), 7.2-8.0 (4H, m)

2- 2-(N,N-Diethylamino)ethoxy!-l-(4-methylbenzo b!-thiophen-5-yl)ethanolhydrochloride Melting point: 189-190° C. NMR (DMSO-d₆) δ value: 1.17(6H, t, J=7.2Hz), 2.57 (3H, s), 2.8-4.0 (10H, m), 4.9-5.3 (1H, m),5.4-5.7 (1H, m), 7.2-8.0 (4H, m)

2- 2-(N,N-Diethylamino)ethoxy!-l-(6-methylbenzo b!-thiophen-5-yl)ethanolhydrochloride Melting point: 144-145° C. NMR (DMSO-d₆) δ value: 1.17(6H, t, J=7.2Hz), 2.41 (3H, s), 2.7-4.1 (10H, m), 4.8-5.3 (1H, m),5.4-5.8 (1H, m), 7.2-8.1 (4H, m)

1-(4-Chlorobenzo b!thiophen-5-yl)-2-2-(N,N-dimethyl-amino)ethoxy!ethanol hydrochloride Melting point:148-149° C. NMR (DMSO-d₆) δ value: 1.17 (6H, t, J=7.2Hz), 2.8-4.1 (10H,m), 5.1-5.4 (1H, m), 5.7-6.0 (1H, m), 7.3-8.2 (4H, m)

1-(6-Chlorobenzo b!thiophen-5-yl)-2- 2-(N,N-diethyl-amino)ethoxy!ethanolhydrochloride Melting point: 140-141° C. NMR (DMSO-d₆) δ value: 1.17(6H, t, J=7.2Hz), 2.6-4.1 (10H, m), 5.0-5.4 (1H, m), 5.7-6.1 (1H, m),7.3-8.2 (4H, m)

2- 2-(N,N-Diethylamino)ethoxy!-1-(2-phenylbenzo b!-thiophen-5-yl)ethanolhydrochloride Melting point: 131-135° C. NMR (DMSO-d₆) δ value: 1.18(6H, t, J=7.lHz), 2.8-4.2 (10H, m), 4.7-5.1 (1H, m), 7.2-8.1 (9H, m)

2- 2-(N,N-Diethylamino)ethoxy!-1-(3-phenylbenzo b!-thiophen-5-yl)ethanolhydrochloride Melting point: 158-160° C. NMR (DMSO-d₆) δ value: 1.14(6H, t, J=7.2Hz), 2.8-4.2 (10H, m), 4.7-5.1 (1H, m), 7.2-8.2 (9H, m)

2- 2-(N,N-Diethylamino)ethoxy!-1-(6-methoxybenzob!-thiophen-5-yl)ethanol hydrochloride Melting point: 161-162° C. NMR(DMSO-d₆), δ value: 1.19 (6H, t, J=7.3Hz), 2.8-4.2 (10H, m), 3.87 (3H,s), 5.1-5.3 (1H, m), 7.2-7.6 (3H, m), 7.92 (1H, s)

1-(4,6-Difluorobenzo b!thiophen-5-yl)-2-2-(N,N-diethylamino)ethoxy!ethanol 1/2 fumarate Melting point: 135-136°C. NMR (DMSO-d₆) δ value: 0.92 (6H, t, J=7.0Hz), 2.4-2.9 (6H, m),3.4-3.9 (4H, m), 5.1-5.5 (3H, m), 6.50 (1H, s), 7.4-7.9 (3H, m)

1-(4-Bromobenzo b!thiophen-5-yl)-2- 2-(N,N-dimethyl-amino)ethoxy!ethanolhydrochloride Melting point: 150-151° C. NMR (CDCl₃) δ value: 1.35 (6H,t, J=7.5Hz), 2.8-4.2 (10H, m), 5.2-5.6 (2H, m), 7.3-7.4 (4H, m)

1-(6-Bromobenzo b!thiophen-5-yl)-2- 2-(N,N-diethyl-amino)ethoxy!ethanolhydrochloride Melting point: 153-154° C. NMR (CDCl₃) δ value: 1.41 (6H,t, J=7.5Hz), 2.6-4.2 (10H, m), 5.3-5.6 (2H, m), 7.2-7.5 (2H, m), 7.99(1H, s), 8.17 (1H, s)

2- 2-(N,N-Di-n-propylamino)ethoxy!-1-(6-fluorobenzo-b!thiophen-5-yl)ethanol Melting point: 143-144° C. NMR (CDCl₃) δ value:0.95 (6H, t, J=7.0Hz), 1.4-2.2 (4H, m), 2.8-3.4 (6H, m), 3.5-4.2 (4H,m), 5.1-5.5 (2H, m), 7.1-7.6 (3H, m), 8.0-8.2 (1H, s)

1-(6-Fluorobenzo b!thiophen-5-yl)-2-(1-piperazinyl)-ethanol Meltingpoint: 172-174° C. NMR (CDCl₃) δ value: 1.4-2.4 (6H, m), 2.6-4.2 (11H,m), 5.2-5.4 (1H, m), 7.1-7.6 (3H, m), 7.9-8.2 (1H, m)

1-(6-Fluorobenzo b!thiophen-5-yl)-2-(1-morpholinyl)-ethanol Meltingpoint: 198-200° C. NMR (DMSO-d₆) δ value: 2.6-4.8 (15H, m), 4.9-5.3 (1H,m), 7.4-8.2 (4H, m)

Production Example 2

(1) To a solution of 8.73 ml of oxalyl chloride in 90 ml of methylenechloride is dropwise added 14.2 ml of dimethyl sulfoxide at -70° C. over30 minutes. The solution is stirred at the same temperature for tenminutes, after which a solution of 11 g of2-(2-chloroethoxy)-1-(6-fluorobenzo b!thiophen-5-yl)ethanol in 90 ml ofmethylene chloride is dropwise added thereto at the same temperatureover 30 minutes. The resulting mixture is stirred at the sametemperature for 30 minutes, and then, 50.2 ml of triethylamine isdropwise added thereto. The temperature of the resulting mixture iselevated to room temperature, and thereafter, 200 ml of diethyl ether isadded thereto. Then, insolubles are removed from the diethyl ether-addedmixture by filtration. Then, the solvent is removed from the resultingfiltrate by distillation under reduced pressure. To the residue obtainedare added 200 ml of water and 200 ml of ethyl acetate, and then, the pHis adjusted to 1 with 1 N hydrochloric acid. Thereafter, the resultingorganic layer is separated, washed successively with water and asaturated saline solution and then dried over anhydrous magnesiumsulfate. The solvent is removed from the thus dried layer bydistillation under reduced pressure. To the residue obtained is added 50ml of diethyl ether, after which insolubles are collected by filtration,to obtain 9.5 g of colorless, solid 2-(2-chloroethoxy)-1-(6-fluorobenzob!thiophen-5-yl)ethanone.

(2) To a solution of 4.5 g of 2-(2-chloroethoxy)-1-(6-fluorobenzob!thiophen-5-yl)ethanone in 45 ml of tetrahydrofuran is added 0.46 g of(R)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine at -10° C.,and thereafter, 9.9 ml of 1 M borane solution of tetrahydrofuran isdropwise added thereto. The temperature of the resulting mixture iselevated to room temperature, and the mixture is stirred at the sametemperature for 1.5 hours, after which 100 ml of water and 100 ml ofethyl acetate are added thereto. The resulting organic layer isseparated, washed successively with water and a saturated salinesolution and then dried over anhydrous magnesium sulfate. The solvent isthen removed from the thus dried layer by distillation under reducedpressure. The residue obtained is purified by a column chromatographyeluent:toluene:ethyl acetate=10:1!, to obtain 4.5 g of oily(+)-2-(2-chloroethoxy)-1-(6-fluoro-benzo b!thiophen-5-yl)ethanol.

(3) In the same manner as in Production Example 1 (2),(+)-1-(6-fluorobenzo b!thiophen-5-yl)-2-2-(N,N-di-ethylamino)ethoxy!ethanol hydrochloride is obtained from(+)-2-(2-chloroethoxy)-1-(6-fluorobenzo b!thiophen-5-yl)-ethanol.

Melting point: 138-139° C. α!_(D) +40.8 (C=1.40, CH₃ OH)

In the same manner, the following compound is obtained:

(-)-1-(6-Fluorobenzo b!thiophen-5-yl)-2-2-(N,N-diethylamino)ethoxy!ethanol hydrochloride Melting point: 138-139°C. α!_(D) -40.3 (C=1.13, CH₃ OH)

An explanation is made below of the NGF activity-potentiating effect ofthe 1,2-ethanediol derivative represented by the general formula I! orits salt.

Nervous Process-Elongating Activity Test Compound

As test compounds, there are used the compounds disclosed inJP-A-3-47,158; JP-A-3-232,830 and JP-A-4-95,070 and the compoundsobtained in Production Examples 1 and 2 which are shown in Tables 1 to6. The melting points of the compounds other than those obtained inProduction Examples 1 and 2 are also shown in Table 7. Incidentally, thecompounds were dissolved in water or dimethyl sulfoxide.

                                      TABLE 1    __________________________________________________________________________    No.       Compound    __________________________________________________________________________       1 #STR4##    2       2 #STR5##    3       3 #STR6##    4       4 #STR7##    5       5 #STR8##    6       6 #STR9##    __________________________________________________________________________

                                      TABLE 2    __________________________________________________________________________    No.       Compound    __________________________________________________________________________       7 #STR10##    8       8 #STR11##    9       9 #STR12##    10       0 #STR13##    11       1 #STR14##    12       2 #STR15##    __________________________________________________________________________

                                      TABLE 3    __________________________________________________________________________    No.       Compound    __________________________________________________________________________    13       3 #STR16##    14       4 #STR17##    15       5 #STR18##    16       6 #STR19##    17       7 #STR20##    18       8 #STR21##    __________________________________________________________________________

                                      TABLE 4    __________________________________________________________________________    No.   Compound    __________________________________________________________________________    19          9 #STR22##    20          0 #STR23##    21          1 #STR24##    22          2 #STR25##    23          3 #STR26##    24          4 #STR27##    __________________________________________________________________________

                                      TABLE 5    __________________________________________________________________________    No.  Compound    __________________________________________________________________________    25         5 #STR28##    26         6 #STR29##    27         7 #STR30##    28         8 #STR31##    29         9 #STR32##    30         0 #STR33##    __________________________________________________________________________

                                      TABLE 6    __________________________________________________________________________    No.       Compound    __________________________________________________________________________    31       1 #STR34##    32       2 #STR35##    33       3 #STR36##    34       4 #STR37##    35       5 #STR38##    36       6 #STR39##    37       7 #STR40##    __________________________________________________________________________

                  TABLE 7    ______________________________________                   Melting point    Compound No.   (° C.)    ______________________________________     1               120-120.5     2             119.5-120.5     3             191.5-192.5     4               180-180.5     5               134-137.5     6             143.5-145     9             207.5-210    10             166.5-167.5    11             232-234    12             191.5-193    13             199-202    14             163-169    15               168-169.5    16             170-173    17             109-110    18               234-234.5    19             155.5-157    20             184-185    21             165-166    22             171-172    23             223-225    24             157-161    ______________________________________

Test Cell

PC12 cell rat adrenal medullary xanthoma (NGF-responding cell)!

Test Medium

RPMI 1640 (mfd. by Nissui pharmaceutical Co., Ltd.) supplemented with10% heat-inactivated (56° C., 30 min.) horse serum (Summit BiotechnologyInc.), 5% heat-inactivated (56° C., 30 min.) fetal calf serum (mfd. byGibco Inc.) and 60 μg/ml of Kanamycine sulfate is used.

Test Method

PC12 cells are adjusted at a density of 8×10³ cells/ml with the aboveculture medium and plated out into 6-well plate (mfd. by Falcon Inc.) ina portion of 2 ml/well. Subsequently, 2.5S-NGF (mfd. by Wako Inc.)dissolved in 0.1% bovine serum albumin/phosphate-buffered salinesolution, is added at a final concentration of 100 ng/ml and the testcompounds are added at final concentration of 10⁻⁵ M at the same time.Cells are incubated at 37° C. in a humidified incubator with 5% CO₂atmosphere. On the 5th day after the treatment of the test compounds,cells from three randomly chosen phase contrast microscope fields arecounted. The proportion of cells bearing neutrites longer than cell bodyto the other cells is determined. Besides, the proportion of the controlgroup free from the test compound is taken as 100%. The results areshown in Table 8.

                  TABLE 8    ______________________________________                 Concentration of                             Nervous process    Compound     test compound                             elongation    No.          added (M)   activity (%)    ______________________________________     1           10.sup.-5   136     2           10.sup.-5   129     3           10.sup.-5   123     4           10.sup.-5   117     5           10.sup.-5   121     6           10.sup.-5   113     7           10.sup.-5   125     8           10.sup.-5   130     9           10.sup.-5   123    10           10.sup.-5   131    11           10.sup.-5   112    12           10.sup.-5   124    13           10.sup.-5   118    14           10.sup.-5   126    15           10.sup.-5   116    16           10.sup.-5   123    17           10.sup.-5   113    18           10.sup.-5   121    19           10.sup.-5   112    20           10.sup.-5   124    21           10.sup.-5   114    22           10.sup.-5   112    23           10.sup.-5   112    24           10.sup.-5   110    25           10.sup.-5   111    26           10.sup.-5   112    27           10.sup.-6   125    28           10.sup.-5   127    29           10.sup.-5   116    30           10.sup.-5   124    31           10.sup.-5   111    32           10.sup.-5   112    33           10.sup.-6   111    34           10.sup.-5   116    35           10.sup.-5   110    36           10.sup.-5   124    37           10.sup.-5   117    ______________________________________

Best Mode for Carrying out the Invention Preparation Example 1 (Tablet)

Tablets each containing 50 mg of 2-2-(N,N-di-ethylamino)ethoxy!-1-(benzo b!thiophen-5-yl)ethanolhydrochloride (Compound No. 1) are prepared by the following methodusing the following recipe:

    ______________________________________    Per one tablet    ______________________________________    Compound No. 1 compound                         50 mg    Milk sugar           20 mg    Kollidon CL (mfd. by BASF)                         15 mg           (1)    Corn starch          30 mg    Avicel (mfd. by Asahi Chemical)                         50 mg    Polyvinylpyrrolidone K-90                         5 mg    Light silicic acid anhydride                         18 mg                                         (2)    Magnesium stearate   2 mg    Total               175 mg    ______________________________________

A mixture of the components (1) is kneaded with 8% aqueous solution ofpolyvinylpyrrolidone K-90, and dried at 60° C., and thereafter, mixedwith the components (2), after which the resulting mixture is tabletedinto circular tablets each having a diameter of 8 mm and a weight of 175mg.

Preparation Example 2 (Capsule)

Capsules each containing 50 mg of 2-2-(N,N-diethylamino)ethoxy!-1-(benzo b!thiophen-5-yl)ethanolhydrochloride (Compound No. 1) are prepared by the following methodusing the following recipe:

    ______________________________________    Per one capsule    ______________________________________    Compound No. 1 compound                            50 mg    Milk sugar              20 mg    Corn starch             53 mg          (1)    Kollidon CL (mfd. by BASF)                            2 mg    Polyvinylpyrrolidone K-90                            5 mg    Avicel PH302 (mfd. by Asahi Chemical)                            18 mg                                           (2)    Magnesium stearate      2 mg    Total                  150 mg    ______________________________________

A mixture of the components (1) is kneaded with 8% aqueous solution ofpolyvinylpyrrolidone K-90, and the resulting mixture is dried at 60° C.and then mixed with the components (2). No. 3 gelatine capsules arefilled with the resulting mixture in a proportion of 150 mg per onecapsule to obtain capsules.

Utilizability in Industry

The 1,2-ethanediol derivative represented by the general formula I! orits salt has a NGF activity-potentiating effect, and is useful as aremedy for various diseases caused by degeneration of central nervoussystem and peripheral nervous system such as senile dementia ofAlzheimer type, Huntington's chorea, various neuropathies, Riley-Daysyndrome, traumatic nerve injury, amyotrophic lateral sclerosis (ALS)and the like.

We claim:
 1. A method of potentiating the activity of a nerve growthfactor, comprising administering an effective amount of an1,2-ethanediol derivative or a salt thereof to a patient in needthereof, wherein said 1,2-ethanediol derivative is represented by thefollowing general formula or its salt: ##STR41## wherein R¹ represents asubstituted or unsubstituted phenyl, naphthyl, indanyl, indenyl ortetrahydronaphthyl group; R² represents a hydrogen atom, a lower alkylgroup or a hydroxyl-protecting group; R³ represents a hydrogen atom or alower alkyl group; nR⁴ 's are the same as or different from one anotherand each represents a hydrogen atom or a lower alkyl group; nR⁵ 's arethe same as or different from one another and each represents a hydrogenatom or a lower alkyl group; R⁶ represents a substituted orunsubstituted nitrogen-containing heterocyclic group; and n represents 0or an integer of 1 to
 6. 2. The method according to claim 1, wherein insaid 1,2-ethanediol derivative or its salt R¹ represents a substitutedor unsubstituted phenyl group; R² represents a hydrogen atom or ahydroxyl-protecting group; nR⁴ 's are the same as or different from oneanother and each represents a hydrogen atom or a lower alkyl group; andnR⁵ 's are hydrogen atoms.
 3. The method according to claim 2, whereinin said 1,2-ethanediol derivative or its salt R¹ is a phenyl,halogen-substituted phenyl, lower alkyl-substituted phenyl or loweralkyl-substituted biphenyl group; R² is a hydrogen atom; nR⁴ 's arehydrogen atoms; and nR⁵ 's are hydrogen atoms.
 4. The method accordingto claim 1, wherein in said 1,2-ethanediol derivative or its salt R¹ isa substituted or unsubstituted naphthyl group; R² is a hydrogen atom ora hydroxyl-protecting group; nR⁴ 's are the same as or different fromone another and each represents a hydrogen atom or a lower alkyl group;nR⁵ 's are hydrogen atoms; R⁶ is a substituted or unsubstitutedpyrrolyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl,quinolyl, quinolidinyl, tetrahydroquinolinyl, quinuclidinyl, thiazolylor thiadiazolyl group.
 5. The method according to claim 4, wherein insaid 1,2-ethanediol derivative or its salt R¹ is a naphthyl group; R² isa hydrogen atom; R³ is a hydrogen atom; nR⁴ 's are hydrogen atoms.